Signal transducer and activator of transcription (STAT) 3 is an important mediator of cytokine signaling and transcriptional regulator of cell proliferation, maturation and survival. It has been described as a key player in cancer development and progression. However, under certain circumstances, STAT3 is also considered a potent tumor suppressor. This contradiction is partially explained by its expression as different isoforms. Alternative splicing gives rise to two STAT3 isoforms, STAT3α and its truncated version STAT3β. Both isoforms are transcriptionally active and display distinct functions under physiological and pathological conditions. In fact, while STAT3α is widely described as an oncogene, STAT3β has gained attention as a potential tumor suppressor. This review by Dagmar Soiber an coworkers in Cytokine provides a concise overview of the current knowledge on STAT3 during tumorigenesis, with special emphasis on the unique and complex roles of its alternatively spliced isoforms.